Substituted benzoylguanidines, process for their preparation, their use as a pharmaceutical or diagnostic, and pharmaceutical containing them

ABSTRACT

Benzoylguanidines of the formula I ##STR1## are described in which: R(1), R(2), R(3), R(4), R(5) are as defined in the specification, and pharmaceutically tolerated salts thereof.

This application is a continuation-in-part of U.S. patent applicationSer. No. 08/252,786 filed Jun. 2, 1994 now abandoned, which isincorporated by reference herein in its entirety.

The invention relates to benzoylguanidines of the formula I ##STR2## inwhich: R(1) is R(6)--CO;

R(6) being (C₁ -C₈)-alkyl, (C₁ -C₈)-perfluoroalkyl, (C₃ -C₈)-alkenyl or--C_(n) H_(2n) --R(9),

n being zero, 1, 2, 3 or 4,

R(9) being (C₃ -C₈)-cycloalkyl, phenyl, biphenylyl or naphthyl, wherethe aromatic radicals are unsubstituted or substituted by 1-3substituents selected from the group consisting of F, Cl, CF₃, methyl,methoxy and NR(10)R(11);

R(10) and R(11) being H, (C₁ -C₄)-alkyl or (C₁ -C₄)-perfluoroalkyl;

R(2) is H, F, Cl, Br, I, OH, CN, NO₂, (C₁ -C₈)-alkyl, (C₁-C₈)-perfluoroalkyl, (C₃ -C₈)-alkenyl or --C_(n) H_(2n) R(15);

n being zero, 1, 2, 3 or 4;

R(15) being (C₃ -C₈)-cycloalkyl, phenyl, biphenylyl or naphthyl, wherethe aromatic radicals are unsubstituted or substituted by 1-3substituents selected from the group consisting of F, Cl, CF₃, methyl,methoxy and NR(16)R(17);

R(16) and R(17) being H, (C₁ -C₄)-alkyl or (C₁ -C₄)-perfluoroalkyl;

or

R(2) is (C₁ -C₉)-heteroaryl, which is linked via C or N and which isunsubstituted or substituted by 1-3 substituents selected from the groupconsisting of F, Cl, CF₃, CH₃, methoxy, hydroxyl, amino, methylamino anddimethylamino;

or

R(2) is SR(18), --OR(18), --NR(18)R(19) or --CR(18)R(19)R(20);

R(18) is --C_(a) H_(2a) --(C₁ -C₉)-heteroaryl, which is unsubstituted orsubstituted by 1-3 substituents selected from the group consisting of F,Cl, CF₃, CH₃, methoxy, hydroxyl, amino, methylamino or dimethylamino;

a is zero, 1 or 2;

R(19) and R(20) independently of each other, are defined as R(18) or arehydrogen, (C₁ -C₄)-alkyl or (C₁ -C₄)-perfluoroalkyl;

or

R(2) is R(21)--SO_(m) or R(22)R(23)N--SO₂ --;

m being 1 or 2;

R(21) being (C₁ -C₈)-alkyl, (C₁ -C₈)-perfluoroalkyl, (C₃ -C₈)-alkenyl or--C_(n) H_(2n) --R(24);

n being zero, 1, 2, 3 or 4;

R(24) being (C₃ -C₈)-cycloalkyl, phenyl, biphenylyl or naphthyl; wherethe aromatic radicals are unsubstituted or substituted by 1-3substituents selected from the group consisting of F, Cl, CF₃, methyl,methoxy and NR(27)R(28);

R(27) and R(28) being H, (C₁ -C₄)-alkyl or (C₁ -C₄)-perfluoroalkyl;

R(22) being H, (C₁ -C₈)-alkyl, (C₁ -C₈)-perfluoroalkyl, (C₃ -C₈)-alkenylor --C_(n) H_(2n) --R(29),

n being zero, 1, 2, 3 or 4;

R(29) being (C₃ -C₈)-cycloalkyl, phenyl, biphenylyl or naphthyl, wherethe aromatic radicals are unsubstituted or substituted by 1-3substituents selected from the group consisting of F, Cl, CF₃, methyl,methoxy and NR(30)R(31);

R(30) and R(31) being H, (C₁ -C₄)-alkyl or (C₁ -C₄)-perfluoroalkyl;

R(23) being H, (C₁ -C₄)-alkyl or (C₁ -C₄)-perfluoroalkyl;

or

R(22) and R(23) together can be 4 or 5 methylene groups of which one CH₂group can be replaced by oxygen, S, NH, N--CH₃ or N-benzyl;

or

R(2) is R(33)X--;

X is oxygen, S, NR(34) or (D═O)A--;

A being oxygen or NR(34);

D being C or SO;

R(33) being (C₁ -C₈)-alkyl, (C₃ -C₈)-alkenyl, (CH₂)_(b) C_(d) F_(2d+1)or --C_(n) H_(2n) --R(36);

b is zero or 1;

d is 1, 2, 3, 4, 5, 6 or 7;

n is zero, 1, 2, 3 or 4;

R(36) is (C₃ -C₈)-cycloalkyl, phenyl, biphenylyl or naphthyl, where thearomatic radicals are unsubstituted or substituted by 1-3 substituentsselected from the group consisting of F, Cl, CF₃, methyl, methoxy andNR(37)R(38);

R(37) and R(38) being H, (C₁ -C₄)-alkyl or (C₁ -C₄)-perfluoroalkyl;

R(34) being H, CH₃ or CF₃ ;

or

R(2) is --SR(40), --OR(40), --NHR(40), --NR(40)R(41), --CHR(40)R(42), --CR(42)R(43)OH!, --C.tbd.CR(45), --CR(46)═CR(45) or -- CR(47) R(48)!_(u)--(CO)-- CR(49)R(50)!_(v) --R(44);

R(40) and R(41) are identical or different and are --(CH₂)_(p)--(CHOH)_(q) --(CH₂)r--(CHOH)_(t) R(51) or --(CH₂)_(p) --O--(CH₂ --CH₂O)_(q) --R(51);

R(51) is hydrogen or methyl;

u is 1, 2, 3 or 4;

v is zero, 1, 2, 3 or 4;

p, q and r are identical or different and are zero, 1, 2, 3 or 4;

t is 1, 2, 3 or 4;

R(42) and R(43) are identical or different and are hydrogen or (C₁-C₆)-alkyl or, together with the carbon atom carrying them, form a (C₃-C₈)-cycloalkyl;

R(44) is H, (C₁ -C₆)-alkyl, (C₃ -C₈)-cycloalkyl or --C_(e) H_(2e)--R(45);

e being zero, 1, 2, 3 or 4;

R(45) is phenyl, which is unsubstituted or substituted by 1-3substituents selected from the group consisting of F, Cl, CF₃, methyl,methoxy and NR(52)R(53);

R(52) and R(53) being H or (C₁ -C₄)-alkyl;

or

R(45) is (C₁ -C₉)-heteroaryl, which is unsubstituted or substituted asphenyl;

or

R(45) is (C₁ -C₆)-alkyl which is unsubstituted or substituted by 1-3 OH;

R(46), R(47), R(48), R(49) and R(50) are hydrogen or methyl;

R(3) is defined as R(1) or R(2);

R(4) and R(5) are, independently of each other, defined as R(2);

and pharmaceutically tolerated salts thereof.

Compounds of the formula I are preferred in which:

R(1) is R(6)--CO;

R(6) being (C₁ -C₈)-alkyl, CF₃ or --C_(n) H_(2n) --R(9);

n being zero, 1, 2, 3 or 4;

R(9) being (C₃ -C₈)-cycloalkyl or phenyl, where phenyl is unsubstitutedor substituted by 1-3 substituents selected from the group consisting ofF, Cl, CF₃, methyl, methoxy and NR(10)R(11);

R(10) and R(11) being H or CH₃ ;

R(2) is H, F, Cl, Br, I, OH, CN, (C₁ -C₈)-alkyl, CF₃, (C₃ -C₈)-alkenylor --C_(n) H_(2n) R(15);

n being zero, 1, 2, 3 or 4;

R(15) being (C₃ -C₈)-cycloalkyl or phenyl, where phenyl is unsubstitutedor substituted by 1-3 substituents selected from the group consisting ofF, Cl, CF₃, methyl, methoxy and NR(16)R(17);

R(16) and R(17) being H or CH₃ ;

or

R(2) is (C₁ -C₉)-heteroaryl, which is linked via C or N and which isunsubstituted or substituted by 1-3 substituents selected from the groupconsisting of F, Cl, CF₃, CH₃, methoxy, hydroxyl, amino, methylamino anddimethylamino;

or

R(2) is SR(18) or --OR(18);

R(18) is --C_(a) H_(2a) --(C₁ -C₉)-heteroaryl, which is unsubstituted orsubstituted by 1-3 substituents selected from the group consisting of F,Cl, CF₃, CH₃, methoxy, hydroxyl, amino, methylamino or dimethylamino;

a is zero, 1 or 2;

or

R(2) is R(21)--SO_(m) ;

m being 2;

R(21) being (C₁ -C₈)-alkyl, CF₃, (C₃ -C₈)-alkenyl or --C_(n) H_(2n)--R(24);

n being zero, 1, 2, 3 or 4;

R(24) being (C₃ -C₈)-cycloalkyl or phenyl, which is unsubstituted orsubstituted by 1-3 substituents selected from the group consisting of F,Cl, CF₃, methyl, methoxy and NR(27)R(28);

R(27) and R(28) being H or CH₃ ;

or

R(2) is R(33)X--;

X is oxygen, S, NR(34) or (C═O)A--;

A being oxygen or NR(34);

R(33) being (C₁ -C₈)-alkyl, (CH₂)_(b) C_(d) F_(2d+1) or --C_(n) H_(2n)--R(36);

b is zero or 1;

d is 1, 2, 3, 4, 5, 6 or 7;

n is zero or 1;

R(36) is (C₃ -C₈)-cycloalkyl or phenyl, which is unsubstituted orsubstituted by 1-3 substituents selected from the group consisting of F,Cl, CF₃, methyl, methoxy and NR(37)R(38);

R(37) and R(38) being H or CH₃ ;

R(34) being H or CH₃ ;

R(3) is defined as R(1) or R(2);

R(4) and R(5) are, independently of each other, defined as R(2),

and pharmaceutically tolerated salts thereof.

Compounds of the formula I are particularly preferred in which:

R(1) is R(6)--CO;

R(6) being (C₁ -C₈)-alkyl, CF₃ or --C_(n) H_(2n) --R(9);

n being zero;

R(9) being (C₃ -C₈)-cycloalkyl or phenyl, where phenyl is unsubstitutedor substituted by 1-3 substituents selected from the group consisting ofF, Cl, CF₃, methyl, methoxy and NR(10)R(11);

R(10) and R(11) being H or CH₃ ;

R(2) is H, F, Cl, Br, I, OH, CN, (C₁ -C₈)-alkyl, CF₃ or --C_(n) H_(2n)R(15);

n being zero, 1 or 2;

R(15) being (C₃ -C₈)-cycloalkyl or phenyl, where phenyl is unsubstitutedor substituted by 1-3 substituents selected from the group consisting ofF, Cl, CF₃, methyl, methoxy and NR(16)R(17);

R(16) and R(17) being H or CH₃ ;

or

R(2) is quinolyl, isoquinolyl, pyrrolyl, pyridyl or imidazolyl, whichare linked via C or N and which are unsubstituted or substituted by 1-3substituents selected from the group consisting of F, Cl, CF₃, CH₃,methoxy, hydroxyl, amino, methylamino and dimethylamino;

or

R(2) is SR(18) or --OR(18);

R(18) is quinolyl, isoquinolyl, pyrrolyl or (CH₂)₀₋₁ -pyridyl, which arelinked via C or N and which are unsubstituted or substituted by 1-3substituents selected from the group consisting of F, Cl, CF₃, CH₃,methoxy, hydroxyl, amino, methylamino or dimethylamino;

or

R(2) is R(33)X--;

X is oxygen, S or NR(34);

R(33) is (C₁ -C₈)-alkyl, (CH₂)_(b) C_(d) F_(2d+1) or --C_(n) H_(2n)--R(36);

b is zero or 1;

d is 1, 2, 3 or 4;

n is zero or 1;

R(36) is phenyl, which is unsubstituted or substituted by 1-3substituents selected from the group consisting of F, Cl, CF₃, methyl,methoxy and NR(37)R(38);

R(37) and R(38) being H or CH₃ ;

R(34) being CH₃ ;

R(3) is defined as R(1) or is H, F, Cl, Br, I, OH, (C₁ -C₈)-alkyl, CF₃or --C_(n) H_(2n) R(15);

n being zero, 1 or 2;

R(15) being (C₃ -C₈)-cycloalkyl or phenyl, which is unsubstituted orsubstituted by 1-3 substituents selected from the group consisting of F,Cl, CF₃, methyl, methoxy and NR(16)R(17);

R(16) and R(17) being H or CH₃ ;

or

R(3) is quinolyl, isoquinolyl, pyrrolyl, pyridyl or imidazolyl, whichare linked via C or N and which are unsubstituted or substituted by 1-3substituents selected from the group consisting of F, Cl, CF₃, CH₃,methoxy, hydroxyl, amino, methylamino and dimethylamino;

or

R(3) is R(21)--SO_(m) ;

m being 2;

R(21) being (C₁ -C₄)-alkyl or CF₃ ;

R(4) and R(5) are, independently of each other, hydrogen, F, Cl, OH,CH₃, CF₃, OMe, OCF₃, OH or NH₂ ;

and pharmaceutically tolerable salts thereof.

Compounds are very especially preferred in which:

R(1) is R(6)--CO;

R(6) being (C₁ -C₂)-alkyl or --C_(n) H_(2n) --R(9);

n being zero;

R(9) being phenyl, where phenyl is unsubstituted or substituted by 1-3substituents selected from the group consisting of F, Cl, CF₃, methyl,methoxy and NR(10)R(11);

R(10) and R(11) being H or CH₃ ;

R(2) is H, F, Cl, Br, I, OH, (C₁ -C₈)-alkyl or --C_(n) H_(2n) R(15);

n being zero, 1 or 2;

R(15) being (C₃ -C₈)-cycloalkyl or phenyl, where phenyl is unsubstitutedor substituted by 1-3 substituents selected from the group consisting ofF, Cl, CF₃, methyl, methoxy and NR(16)R(17);

R(16) and R(17) being H or CH₃ ;

or

R(2) is quinolyl, isoquinolyl, pyrrolyl, pyridyl or imidazolyl, whichare linked via C or N and which are unsubstituted or substituted by 1-3substituents selected from the group consisting of F, Cl, CF₃, CH₃,methoxy, hydroxyl, amino, methylamino and dimethylamino;

or

R(2) is SR(18) or --OR(18);

R(18) is quinolyl, isoquinolyl, pyrrolyl or (CH₂)₀₋₁ -pyridyl, which arelinked via C or N and which are unsubstituted or substituted by 1-3substituents selected from the group consisting of F, Cl, CF₃, CH₃,methoxy, hydroxyl, amino, methylamino or dimethylamino;

or

R(2) is R(33)X--;

X is oxygen;

R(33) is (C₁ -C₆)-alkyl or --C_(n) H_(2n) --R(36);

n is zero or 1;

R(36) is phenyl, which is unsubstituted or substituted by 1-3substituents selected from the group consisting of F, Cl, CF₃, methyl,methoxy and NR(37)R(38);

R(37) and R(38) being H or CH₃ ;

R(3) is H, F, Cl, Br, I or --C_(n) H_(2n) R(15);

n being zero, 1 or 2;

R(15) being (C₃ -C₈)-cycloalkyl or phenyl, which is unsubstituted orsubstituted by 1-3 substituents selected from the group consisting of F,Cl, CF₃, methyl, methoxy and NR(16)R(17);

R(16) and R(17) being H or CH₃ ;

or

R(3) is R(21)--SO_(m) ;

m being 2;

R(21) being (C₁ -C₄)-alkyl;

R(4) and R(5) are, independently of each other, hydrogen, F, Cl, OH,CH₃, CF₃, OMe, OCF₃, OH or NH₂ ;

and pharmaceutically tolerable salts thereof.

(C₁ -C₉)-Heteroaryl is to be understood as meaning, in particular,radicals which are derived from phenyl or naphthyl and in which one ormore CH groups are replaced by N and/or in which at least two adjacentCH groups (while forming a five-membered aromatic ring) are replaced byS, NH or O. Moreover, it is also possible for one or both atoms of thecondensation site of bicyclic radicals (as in indolizinyl) to be Natoms.

Heteroaryl means, in particular, furanyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl,indazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl,quinazolinyl or cinnolinyl.

If one of the substituents R(1) to R(60) contains one or more asymmetriccenters, they can have either the S or the R configuration. Thecompounds can exist as optical isomers, diastereomers, racemates ormixtures of these.

The alkyl radicals which have been mentioned can be straight-chain orbranched.

The invention furthermore relates to a process for the preparation ofthe compound I, which comprises reacting compounds of the formula II##STR3## with guanidine, R(1) to R(5) having the abovementioned meaningand L being a leaving group which can readily be substituted by anucleophile.

The activated acid derivatives of the formula II, in which L is analkoxy group, preferably a methoxy group, a phenoxy group, a phenylthio,methylthio or 2-pyridylthio group, or a nitrogen heterocycle, preferably1-imidazolyl, are obtained advantageously in a manner known per se fromthe carbonyl chlorides (formula II, L═Cl) on which they are based andwhich, in turn, can be prepared in a manner known per se from thecarboxylic acids (formula II, L═OH) on which they are based, for examplethionyl chloride.

In addition to the carbonyl chlorides of the formula II (L═Cl), otheractivated acid derivatives of the formula II can also be prepared, in amanner known per se, directly from the benzoic acid derivatives (formulaII, L═OH) on which they are based, for example the methyl esters of theformula II where L═OCH₃ by treatment with gaseous HCl in methanol, theimidazolides of the formula II by treatment with carbonyldiimidazoleL=1-imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962)!,the mixed anhydrides II with Cl-COOC₂ H₅ or tosyl chloride in thepresence of triethylamine in an inert solvent, and benzoic acids can beactivated with dicyclohexylcarbodiimide (DCC) or with O-(cyano(ethoxycarbonyl)methylene)amino!-1,1,3,3-tetramethyluroniumtetrafluoroborate ("TOTU") Proceedings of the 21. European PeptideSymposium, Peptides 1990, Editors E. Giralt and D. Andreu, Escom,Leiden, 1991!. A series of suitable methods for the preparation ofactivated carboxylic acid derivatives of the formula II can be found inJ. March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons,1985), p. 350, where the source references are cited.

An activated carboxylic acid derivative of the formula II is reactedwith guanidine in a manner known per se in a protic or aprotic polar,but inert, organic solvent. Methanol, isopropanol or THF have proventhemselves in the reaction of the methyl benzoates (11, L═OMe) withguanidine, the temperatures being 20° C. to the boiling point of thesesolvents. In most reactions of compounds II with salt-free guanidine,the process was advantageously carried out in aprotic inert solvents,such as THF, dimethoxyethane or dioxane. Water, together with a base,such as, for example, NaOH, can also be used as solvent in the reactionof II with guanidine.

If L═Cl, the process is carried out advantageously with the addition ofan acid scavenger, for example in the form of excess guanidine, to bindthe hydrohalic acid.

Some of the basic benzoic acid derivatives of the formula II are knownand described in the literature. The unknown compounds of the formula IIcan be prepared by methods known from the literature. The benzoic acidsobtained are reacted by one of the above-described process variants togive compounds I according to the invention.

Some substituents can successfully be introduced into the 3-, 4- and5-position by methods which are known from the literature, namelypalladium-mediated cross coupling of aryl halides or aryl triflateswith, for example, organostannanes, organoboric acids or organoboranes,or organocopper or organozinc compounds.

In general, benzoylguanidines are weak bases and can bind acid with theformation of salts. Suitable acid addition salts are salts of allpharmacologically acceptable acids, for example halides, in particularhydrochlorides, lactates, sulfates, citrates, tartrates, acetates,phosphates, methylsulfonates and p-toluenesulfonates.

The compounds I are substituted acylguanidines.

The best-known representative of the acylguanidines is the pyrazinederivative amiloride, which is used in therapy as a potassium-sparingdiuretic. A large number of other amiloride-type compounds are describedin the literature, for example dimethylamiloride orethylisopropylamiloride. ##STR4## Amiloride: R', R"═H Dimethylamiloride:R', R"═CH,

Ethylisopropylamiloride: R'═C₂ H₅, R"═CH(CH₃)₂

Moreover, tests are known which suggest that amiloride hasantiarrhythmic properties (Circulation 79, 1257-63 (1989)). However, itsbroad use as an antiarrhythmic is restricted by the fact that thiseffect is only weakly pronounced and is accompanied by a hypotensive andsaluretic activity, and these side effects are undesired in thetreatment of cardiac arrhythmias.

Experiments on isolated animal hearts have also suggested that amiloridehas antiarrhythmic properties (Eur. Heart J. 9 (suppl. 1): 167 (1988)(book of abstracts)). For example, it has been found on rats' heartsthat artificially induced ventricular fibrillation can be suppressedcompletely by amiloride. In this model, the abovementioned amiloridederivative ethylisopropylamiloride was even more potent than amilorideitself.

U.S. Pat. No. 5,091,394 (HOE 89/F 288) describes benzoylguanidines whichcarry a hydrogen atom in the position which corresponds to the radicalR(1). German Patent Application P 42 04 575.4 (HOE 92/F 034), now U.S.Pat. No. 5,373,024 proposes benzoylguanidines in which, however, thesubstituents do not have the meanings claimed in the present invention.

U.S. Pat. No. 3,780,027 claims acylguanidines whose structure is similarto those of the compounds I and which are derived from commerciallyavailable loop diuretics, such as bumetanide. Accordingly, a powerfulsalidiuretic activity of these compounds is reported.

It was therefore surprising that the compounds according to theinvention have no undesired, disadvantageous salidiuretic properties,but have a very good activity against arrhythmias as they occur, forexample, in connection with oxygen deficiencies. Due to theirpharmacological properties, the compounds are highly suitable for use asantiarrhythmics with a cardioprotective component for the prophylaxisand treatment of cardiac infarctions and for the treatment of anginapectoris, in which context they also preventively inhibit, or reducegreatly, the pathophysiological processes in the formation ofischemia-induced damage, in particular when ischemia-induced cardiacarrhythmias are triggered. Due to inhibition of the cellular Na⁺ /H⁺exchange mechanism, the compounds of the formula I according to theinvention, which have a protective activity against pathological hypoxicand ischemic situations, can be used as pharmaceuticals for thetreatment of all acute or chronic damage triggered by ischemia or forthe treatment of directly or collaterally induced diseases. This appliesto their use as pharmaceuticals for surgical interventions, for examplein connection with organ transplants, where the compounds can be usedfor the protection of the organs in the donor before and during theirremoval, for the protection of removed organs, for example in theirtreatment with, or storage in, physiological bathing fluids, and for thetransfer into the recipient organism. Equally, the compounds arevaluable protective pharmaceuticals when angioplastic surgicalinterventions are carried out, for example on the heart or on peripheralblood vessels. In correspondence with their protective activity againstischemia-induced damage, the compounds are also suitable aspharmaceuticals for the treatment of ischemias of the nervous system, inparticular of the central nervous system, where they are suitable, forexample, for the treatment of stroke or of brain edema. Moreover, thecompounds of the formula I according to the invention are also suitablefor the treatment of forms of shock, for example allergic, cardiogenic,hypovolemic and bacterial shock.

Moreover, the compounds of the formula I according to the invention aredistinguished by a powerful inhibitory action on cell proliferation, forexample fibroblast cell proliferation and proliferation of the smoothvascular muscle cells. This is why the compounds of the formula I aresuitable as valuable therapeutic agents for diseases in which cellproliferation is a direct or collateral cause, and they can therefore beused as antiatherosclerotics, agents against diabetic latecomplications, cancers, fibrotic disorders, such as pulmonary fibrosis,hepatic fibrosis or renal fibrosis, organ hypertrophies andhyperplasias, in particular in prostatic hyperplasia or prostatichypertrophy.

The compounds according to the invention are valuable inhibitors of thecellular sodium/proton antiporter (Na⁺ /H⁺ exchanger), which is elevatedin a large number of diseases (essential hypertension, atherosclerosis,diabetes and the like) even in those cells which are readily accessibleto measurements, such as in erythrocytes, thrombocytes or leucocytes.The compounds according to the invention are therefore suitable asoutstanding and simple scientific tools, for example in their use asdiagnostics for determining, and distinguishing between, particularforms of hypertension, and also of atherosclerosis, diabetes,proliferative disorders and the like. Moreover, the compounds of theformula I are suitable for preventive therapy for preventing the genesisof hypertension, for example of essential hypertension.

In contrast to the known compounds, the solubility in water of thecompounds according to the invention is significantly improved. They aretherefore much better suited to intravenous administration.

Pharmaceuticals which contain a compound I can be administered orally,parenterally, intravenously, rectally or by inhaling, the preferred wayof administration depending on the particular symptom of the disease.The compounds I can be used by themselves or together withpharmaceutical auxiliaries, and they can be employed both in veterinarymedicine and human medicine.

A person skilled in the art knows, on the basis of his expert knowledge,which auxiliaries are suitable for the desired pharmaceuticalformulation. Auxiliaries which can be used in addition to solvents, gelformers, bases for suppositories, tableting auxiliaries, and otherexcipients for active substances are, for example, antioxidants,dispersants, emulsifiers, antifoams, flavor improvers, preservatives,solubilizers or colorants.

For an oral dosage form, the active compounds together with the suitableadditives, such as carriers, stabilizers or inert diluents, are mixedand formulated by customary methods to give suitable dosage forms, suchas tablets, sugar-coated tablets, hard gelatin capsules, or aqueous,alcoholic or oily solutions. Inert excipients which can be used are, forexample, gum arabic, magnesia, magnesium carbonate, potassium phosphate,lactose, glucose or starch, in particular corn starch. Dry granules ormoist granules can be used for the preparation. Examples of oilycarriers or examples of solvents are vegetable or animal oils, such assunflower oil or cod liver oil.

For subcutaneous or intravenous administration, the active compounds, ifdesired together with the substances which are customary for thispurpose, such as solubilizers, emulsifiers or other auxiliaries, aredissolved, suspended or emulsified. Examples of suitable solvents are:water, physiological saline or alcohols, for example ethanol, propanol,glycerol, and also sugar solutions, such as glucose or mannitolsolutions, or else a mixture of the various solvents which have beenmentioned above.

Pharmaceutical formulations which are suitable for administration in theform of aerosols or sprays are, for example, solutions, suspensions oremulsions of the active substance of the formula I in a pharmaceuticallyacceptable solvent, such as, in particular, ethanol or water, or else ina mixture of such solvents.

If required, the formulation can also contain other pharmaceuticalauxiliaries, such as surfactants, emulsifiers and stabilizers, and apropellent gas. The concentration of active substance in such apreparation is generally from about 0.1 to 10, in particular from about0.3 to 3% by weight.

The dose of the active substance of the formula I to be administered andthe frequency of administration will depend on the power and duration ofaction of the compounds used; in addition also on the nature andseverity of the disease to be treated and on the sex, age, weight andindividual responsiveness of the mammal to be treated.

On average, the daily dosage rate of a compound of the formula I in thecase of a patient of approximately 75 kg will be at least 0.001 mg/kg,preferably 0.01 mg/kg, up to not more than 10 mg/kg, preferably 1 mg/kg,of body weight. If the disease is acute, such as immediately aftersuffering a cardiac infarction, even higher and, in particular, morefrequent, doses may be required, for example up to 4 single doses perday. In particular, for intravenous administration, such as in the caseof a patient who has suffered an infarction and is under intensive care,up to 200 mg per day may be required.

List of abbreviations

    ______________________________________                                        MeOH         methanol                                                         DMF          N,N-dimethylformamide                                            EI           electron impact                                                  DCI          desorption-chemical ionization                                   RT           room temperature                                                 EA           ethyl acetate (EtOAc)                                            mp           melting point                                                    HEP          n-heptane                                                        ES           electron spray                                                   FAB          fast atom bombardment                                            CH.sub.2 Cl.sub.2                                                                          dichloromethane                                                  THF          tetrahydrofuran                                                  eq.          equivalent                                                       mol %        mol percent                                                      (dppf)       1,1-bis(diphenylphosphino)ferrocene                              AIBN         azobisisobutyronitrile                                           ______________________________________                                    

Experimental part

General instructions for preparing benzoylguanidines (I)

Variant A: from benzoic acids (11, L═OH)

1.0 eq. of the benzoic acid derivative of the formula II is dissolved orsuspended in anhydrous THF (5 ml/mmol) and 1.1 eq. ofcarbonyldiimidazole are then added. After stirring at RT for 2 hours,5.0 eq. of guanidine are introduced into the reaction solution. Afterstirring overnight, the THF is distilled off under reduced pressure(rotary evaporator), water is added, the pH is adjusted to from 6 to 7with 2N HCl and the corresponding benzoylguanidine (formula I) isfiltered off. The benzoylguanidines thus obtained can be converted intothe corresponding salts by treatment with aqueous, methanolic orethereal hydrochloric acid or other pharmacologically tolerated acids.

General instructions for preparing benzoylguanidines (I)

Variant B: from alkyl esters of benzoic acid (11, L═O-alkyl)

1.0 ,eq. of the benzoic acid alkyl ester of the formula II and 5.0 eq.of guanidine (free base) are dissolved in isopropanol or suspended inTHF and boiled under reflux (typical reaction time, 2 to 5 h) untiltransformation is complete (monitoring by thin layer chromatography).The solvent is distilled off under reduced pressure (rotary evaporator),and the residue is taken up in EE and washed 3× with NaHCO₃ solution.Drying then takes place over Na₂ SO₄, the solvent is distilled off invacuo, and chromatography takes place on silica gel using a suitableeluent, e.g. EA/MeOH 5:1. (Salt formation, compare Variant A)

Example 1: 3-Acetyl-4-hydroxybenzoylguanidine

1a)

4-Acetoxybenzoic acid was converted by Fries displacement, with 3 eq. ofAlCl₃ at 140° C., into 3-acetyl-4-hydroxybenzoic acid.

1b)

1.0 eq. of 3-acetyl-4-hydroxybenzoic acid was reacted in accordance withVariant A with 1.1 eq. of carbonyldiimidazole and 5 eq. of guanidine.Colorless crystals, mp 218°-221° C.

Example 2: 3-Acetyl-4-methoxybenzoylguanidine hydrochloride

2a)

1.0 eq. of 3-acetyl-4-hydroxybenzoic acid preparation, see 1a)! wasreacted with 2.2 eq. each of K₂ CO₃ and methyl iodide in absoluteacetone to form methyl 3-acetyl-4-methoxybenzoate. Colorless crystals,mp 54°-58° C.

2b)

The ester from 2a) was reacted with guanidine in accordance with VariantB. Colorless crystals, mp 156°-162° C. The hydrochloride was prepared inaccordance with Variant A. Colorless crystals, mp 206°-212° C.

Example 3: 3-Acetyl-4-isopropoxybenzoylguanidine hydrochloride

3a)

1.0 eq. of 3-acetyl-4-hydroxybenzoic acid was reacted with 2.2 eq. eachof K₂ CO₃ and isopropyl bromide in absolute DMF to form isopropyl3-acetyl-4-isopropoxybenzoate. Yellowish oil, MS (ES): 265 (M+1).

3b)

The ester from 3a) was reacted with guanidine in accordance with VariantB and converted into the hydrochloride. Colorless crystals, mp 158°-170°C.

Example 4: 3-Acetyl-4-benzyloxybenzoylguanidine hydrochloride

4a)

1.0 eq. of methyl 3-acetyl-4-hydroxybenzoate was reacted with 1.1 eq.each of K₂ CO₃ and benzyl bromide in absolute DMF to form methyl3-acetyl-4-benzyloxybenzoate. Colorless crystals, mp 68°-72° C.

4b)

The ester from 4a) was reacted with guanidine in accordance with VariantB and isolated as the hydrochloride. Colorless crystals, mp 175°-182° C.

Example 5: 3-Acetyl-5-bromo-4-hydroxybenzoylguanidine hydrochloride

Methyl 3-acetyl-5-bromo-4-hydroxybenzoate, which is known from theliterature, was converted into the benzoylguanidine in accordance withVariant B and isolated as the hydrochloride. Colorless crystals, mp 230°C. (with decomposition).

Example 6: 3-Acetylbenzoylguanidine hydrochloride

1.0 eq. of 3-acetylbenzoic acid was reacted in accordance with Variant Awith 1.1 eq. of carbonyldiimidazole and 5 eq. of guanidine, and isolatedas the hydrochloride. Colorless crystals, mp 202°-204° C.

Example 7: 3-Benzoylbenzoylguanidine hydrochloride

1.0 eq. of 3-benzoylbenzoic acid was reacted in accordance with VariantA with 1.1 eq. of carbonyldiimidazole and 5 eq. of guanidine, andisolated as the hydrochloride. Colorless crystals, mp 150°-154° C.

Example 8: 3-Acetyl-4-isopropylbenzoylguanidine hydrochloride

8a)

Methyl 3-acetyl-4-hydroxybenzoate was converted, in CH₂ Cl₂, into the4-triflate using pyridine and trifluoromethanesulfonic anhydride.Yellowish oil, MS (ES): 327 (M+1).

8b)

1.0 eq. of the triflate from 8a) was dissolved in THF and 3 mol % ofPdCl₂ (dppf) and 4 mol % of copper(I) iodide were added. 1.5 eq. ofisopropyl/zinc chloride (prepared from the Grignard reagent and zincchloride) were added to this suspension, which was stirred at RT.Standard working up with 1N HCl yielded, after working up by columnchromatography, methyl 3-acetyl-4-isopropylbenzoate. Oil, MS (ES): 221(M+1).

8c)

The methyl benzoate derivative from 8b) was hydrolyzed under standardconditions (MeOH/NaOH), and the resulting benzoic acid was convertedinto the guanidide in accordance with Variant A, and isolated as thehydrochloride. Colorless crystals, mp 107°-118° C.

Example 9: 3-Acetyl-4-isobutylbenzoylguanidine hydrochloride

Was prepared in analogy with Example 8. Colorless crystals, mp 124°-130°C.

Example 10: 3-Acetyl-4-cyclopentylbenzoylguanidine hydrochloride

Was prepared in analogy with Example 8. Colorless crystals, mp 148°-154°C.

Example 11: 3-Acetyl-4-(2,2-dimethylpropyl)benzoylguanidinehydrochloride

Was prepared in analogy with Example 8. Colorless crystals, mp 138°-148°C.

Example 12: 3-Acetyl-4-fluorobenzoylguanidine hydrochloride

12a)

In accordance with a method known from the literature, methyl3-bromo-4-fluorobenzoate is reacted, under (Ph₃ P)₂ PdCl₂ catalysis,with (trimethylsilyl)acetylene to form methyl4-fluoro-3-(2-trimethylsilylethinyl)benzoate. MS (ES): 251 (M+1).

12b)

The product from 12a) is reacted, in 90% acetic acid and in the presenceof concentrated sulfuric acid, with mercuric acetate to form methyl3-acetyl-4-fluorobenzoate. MS (ES): 198 (M+1).

12c)

The methyl benzoate derivative from 12b) was hydrolyzed under standardconditions (MeOH/NaOH) and the resulting benzoic acid converted into theguanidide in accordance with Variant A and isolated as thehydrochloride. Colorless crystals, mp 178°-185° C.

Example 13: 3-Acetyl-4-imidazolylbenzoylguanidine hydrochloride

1.0 eq. of 3-acetyl-4-fluorobenzoylguanidine hydrochloride was reacted,in DMF and in the presence of 1.1 eq. of K₂ CO₃, with 2 eq. of imidazoleto form the 4-imidazolyl derivative, and isolated as the hydrochloride.Colorless crystals, mp>240° C.

Example 14: 3-Acetyl-4-(2,4-difluorophenoxy)benzoylguanidinehydrochloride

14a)

1.0 eq. of methyl 3-acetyl-4-fluorobenzoate preparation, see Example12b)! was reacted, in DMF and in the presence of 1.1 eq. of K₂ CO₃ and1.3 eq. of 2,4-difluorophenol, to form methyl3-acetyl-4-(2,4-difluorophenol)benzoate. Colorless crystals, mp 85°-87°C.

14b)

The methyl benzoate derivative from 14a) was hydrolyzed under standardconditions (MeOH/NaOH) and the resulting benzoic acid was converted intothe guanidide in accordance with Variant A, and isolated as thehydrochloride. Colorless crystals, mp 188°-196° C.

Example 15: 3-Acetyl-4-(4-fluorophenoxy)benzoylguanidine hydrochloride

Was prepared in analogy with Example 14. Colorless crystals, mp200°-210° C.

Example 16: 3-Acetyl-4- 2-(6-methyl)pyridylmethoxy!benzoylguanidinehydrochloride

16a)

1.2 eq. of trifluoromethanesulfonic anhydride were added, at -30° C., to1 eq. of methyl 3-acetyl-4-hydroxybenzoate, 1.2 eq. of2,6-dimethylpyridine and 0.2 eq. of DMAP in CH₂ Cl₂, and the mixture wasstirred at RT for 2 h. Adding a saturated solution of NaHCO₃, extractingby shaking three times with EA, drying over MgSO₄ and concentrating invacuo yielded a yellow oil as the crude product. This was taken up inDMF, 1 eq. of 5-hydroxyquinoline and K₂ CO₃ were added, and the mixturewas heated to 120° C. After working up with a saturated solution ofNaHCO₃ /EA, purification was carried out using column chromatography.Methyl 3-acetyl-4- 2-(6-methyl)pyridylmethoxy!benzoate was isolated. MS(ES): 300 (M+1).

16b)

The benzoic ester derivative from 16a) was converted into the guanididein accordance with Variant A. MS (ES): 327 (M+1).

Example 17: 3-Acetyl-5-methylsulfonylbenzoylguanidine hydrochloride

17a)

3-Bromobenzoic acid was converted into the corresponding3-chlorosulfonic acid by treatment with chlorosulfonic acid. Subsequenthydrolysis, conversion into the disodium salt, and dimethylation withmethyl iodide in DMF, resulted in methyl5-bromo-3-methylsulfonylbenzoate. Crystals, mp 82°-85° C.

17b)

The benzoic ester derivative from 17a) was converted into methyl3-acetyl-5-methylsulfonylbenzoate in analogy with Example 12a) and 12b).Colorless crystals, mp 106°-108° C.

17c)

The ester from 17b) was converted into the guanidide in accordance withVariant B, and subsequently isolated as the hydrochloride. Colorlesscrystals, mp 221°-223° C.

Example 18: 3-Acetyl-6-hydroxybenzoylguanidine hydrochloride

1.0 eq. of 3-acetyl-6-hydroxybenzoic acid was reacted with 1.1 eq. ofcarbonyldiimidazole and 5 eq. of guanidine in accordance with Variant A,and isolated as the hydrochloride. Colorless crystals, mp 170°-180° C.

Example 19: 3-Acetyl-5-bromo-4-hydroxybenzoylguanidine hydrochloride

19a)

Methyl 3-acetyl-4-hydroxybenzoate was reacted in chlorobenzene with 1.1eq. of N-bromosuccinimide and a trace of AlBN to form methyl3-acetyl-5-bromo-4-hydroxybenzoate. Colorless crystals, mp 106°-108° C.

19b)

The ester from 19a) was converted into the guanidide in accordance withVariant B, and isolated as the hydrochloride. Crystals, mp 230° C. withdecomposition.

Example 20: 3-Acetyl-5-chloro-4-hydroxybenzoylguanidine hydrochloride

20a)

1 eq. of 4-acetoxy-3-chlorobenzoic acid was mixed with 3 eq. of AlCl₃,and the mixture was heated at 140° C. for 1 h. Working up with 2N HClresulted in 3-acetyl-5-chloro-4-hydroxybenzoic acid. Yellow crystals, mp226°-234° C.

20b)

The benzoic acid from 20a) was converted into the guanidide inaccordance with Variant A, and isolated as the hydrochloride. Yellowishcrystals, mp 198°-203° C.

Example 21: 3-Acetyl-5-bromo-4-methoxybenzoylguanidine hydrochloride

21a)

1 eq. of methyl 3-acetyl-5-bromo-4-hydroxybenzoate (preparation, seeExample 19) was reacted, in acetone, with 2.0 eq. of K₂ CO₃ and 2.1 eq.of methyl iodide to give methyl 3-acetyl-5-bromo-4-methoxybenzoate.Colorless oil, MS (ES): 288 (M+1).

21b)

The 4-methoxybenzoic ester from 21a) was hydrolyzed under standardconditions (MeOH/NaOH), and the resulting benzoic acid derivative wasconverted into the guanidide in accordance with Variant A, and isolatedas the hydrochloride. Colorless crystals, mp 175°-178° C.

Example 22: 3-Acetyl-5-bromo-4-isopropoxybenzoylguanidine hydrochloride

Was prepared in analogy with Example 21. Colorless crystals, mp158°-170° C.

Example 23: 3-Acetyl-5-bromo-4-benzyloxybenzoylguanidine hydrochloride

Was prepared in analogy with Example 21. Colorless crystals, mp175°-182° C.

Example 24: 3-Acetyl-5-cyclopentyl-4-methoxybenzoylguanidinehydrochloride

24a)

Methyl 3-acetyl-5-bromo-4-methoxybenzoate was reacted, in accordancewith Example 8b) and with mediation of PdCl₂ (dppf), withcyclopentylzinc chloride (Br⁻ instead of CF₃ SO₃ ⁻ as the leavinggroup). Yellow oil, MS (ES): 277 (M+1).

24b)

The product from 24a) was hydrolyzed under standard conditions(MeOH/NaOH), and the resulting benzoic acid derivative was convertedinto the guanidide in accordance with Variant A, and isolated as thehydrochloride. Colorless oil, MS (ES): 304 (M+1).

Example 25: 3-Acetyl-4-(3-pyridinyl)-benzoylguanidine ##STR5##

a) 5-Bromo-2-fluoro-acetophenone

4.1 g of 2-fluoroacetophenone are dissolved in 16 ml concentrated H₂ SO₄at room temperature and then 4.3 g dibromocyanuric acid, dissolved in in24 ml of concentrated H₂ SO₄, are added dropwise. The mixture wasstirred for 1 h at RT. Then the mixture is poured on about 100 g of ice,and the solution is extracted 3× with 100 ml of CH₂ Cl₂. Drying thentakes place over Na₂ SO₄ and the solvent is distilled off in vacuo. Abrown oil results which is distilled in vacuo. boiling point 90° C. (1Torr). After distillation 2.8 g of a colorless oil are obtained. MS(El): 217 (M+H)⁺

b) 3-Acetyl-4-fluoro-benzoic acid n-butylester

2.4 g of 5-bromo-2-fluoro-acetophenone, 5.2 ml of n-tributylamine, 70 mgof palladium(II)acetate and 1,3-bis(diphenylphosphino)propane aredissolved in 10 ml of n-butanol and 20 ml DMF, and the mixture wasstirred 8 h at 100° C. under CO-atmosphere. The mixture is poured into200 ml of a saturated aqueous solution of NaHSO₄, and the mixture isextracted 3 times with 100 ml MTB. Drying takes place over Na₂ SO₄ andthe solvent is removed in vacuo. Chromatography over kieselgel withMTB/DIP 1:1 affords 1,6 g of a colorless oil. R_(f) (MTB/DIP 1:1)=0.38MS (DCl): 239 (M+H)⁺

c) 3-acetyl-4-(3-pyridinyl)-benzoic acid n-butylester

1.5 g of 3-acetyl-4-fluoro-benzoic acid n-butylester, 0.6 g of3-hydroxypyridine and 4.1 g of Cs₂ CO₃ are stirred in 20 ml oftetramethylurea for 2 h at 110° C. After cooling to RT the mixture ispoured into 200 ml EE and the mixture is washed 3 times with 100 mlbrine. Drying takes place over Na₂ SO₄ and the solvent is distilled offin vacuo. Chromatography over silica gel with MTB furnishes 1.3 g of apale yellow oil. R_(f) (MTB)=0.30 MS (DCl): 314 (M+H)⁺

d) 3-Acetyl-4-(3-pyridinyl)-benzoylguanidine

1.2 g of 3-acetyl-4-(3-pyridinyl)-benzoic acid n-butylester areconverted into the guanidine in isopropanol in accordance with VariantB. Chromatography over silica gel with EE/MeOH 10:1 furnishes 360 mg ofan amorphous solid. This solid is dissolved in 50 ml of 0.1N aqueousHCl-solution and the water and the HCl are removed in vacuo. Thedihydrochloride is obtained. mp 165° C. (decomposition). R_(f) (EE/MeOH10:1)=0.15 MS (ES): 299 (M+H)⁺

Pharmacological data

Inhibition of the Na⁺ /H⁺ exchanger of rabbit erythrocytes

New Zealand White rabbits (Ivanovas) were given a standard dietcontaining 2% cholesterol for six weeks in order to activate Na⁺ /H⁺exchange and thus to be able to determine, by flame photometry, theinflux of Na⁺ into the erythrocytes by way of Na⁺ /H⁺ exchange. Theblood was removed from the aural arteries and rendered incoagulable with25 IU of potassium heparin. A portion of each sample was used todetermine the hematocrit in duplicate by centrifugation. Aliquots of 100μl in each case were used for measuring the initial content of Na⁺ inthe erythrocytes.

In order to determine the amiloride-sensitive sodium influx, 100 μl ofeach blood sample were in each case incubated in 5 ml of a hyperosmolarsalt/sucrose medium (mmol/l: 140 NaCl, 3 KCl, 150 sucrose, 0.1 ouabain,20 tris-hydroxymethylaminomethane) at pH 7.4 and 37° C. After that, theerythrocytes were washed three times with ice-cold MgCl₂ /ouabainsolution (mmol/l: 112 MgCl₂, 0.1 ouabain), and hemolyzed in 2.0 ml ofdistilled water. The intracellular content of sodium was determined byflame photometry.

The net influx of Na⁺ was calculated from the difference between theinitial sodium values and the sodium content of the erythrocytesfollowing incubation. The amiloride-inhibitable sodium influx wasobtained from the difference in the sodium content of the erythrocytesfollowing incubation with and without 3×10⁻⁴ mol/l amiloride. The sameprocedure was used for the compounds according to the invention.

Results

Inhibition of the Na⁺ /H⁺ exchanger:

    ______________________________________                                               Example                                                                              IC.sub.50  mol/l                                                ______________________________________                                               1      2.0 × 10.sup.-6                                                  2      1.0 × 10.sup.-6                                                  3      1.1 × 10.sup.-6                                                  4      1.2 × 10.sup.-6                                           ______________________________________                                    

We claim:
 1. A benzoylguanidine of the formula I ##STR6## in which: R(1)is R(6)--CO;R(6) being (C₁ -C₈)-alkyl, (C₁ -C₈)-perfluoroalkyl, (C₃-C₈)-alkenyl or --C_(n) H_(2n) --R(9),n being zero, 1, 2, 3 or 4, R(9)being (C₃ -C₈)-cycloalkyl, phenyl, biphenylyl or naphthyl, where thearomatic radicals are unsubstituted or substituted by 1-3 substituentsselected from the group consisting of F, Cl, CF₃, methyl, methoxy andNR(10)R(11);R(10) and R(11) being H, (C₁ -C₄)-alkyl or (C₁-C₄)-perfluoroalkyl; R(2) is H, F, Cl, Br, I, OH, CN, NO₂, (C₁-C₈)-alkyl, (C₁ -C₈)-perfluoroalkyl, (C₃ -C₈)-alkenyl or --C_(n) H_(2n)R(15);n being zero, 1, 2, 3 or 4; R(15) being (C₃ -C₈)-cycloalkyl,phenyl, biphenylyl or naphthyl, where the aromatic radicals areunsubstituted or substituted by 1-3 substituents selected from the groupconsisting of F, Cl, CF₃, methyl, methoxy and NR(16)R(17);R(16) andR(17) being H, (C₁ -C₄)-alkyl or (C₁ -C₄)-perfluoroalkyl; or R(2) isR(21)--SO_(m) or R(22)R(23)N--SO₂ --;m being 1 or 2; R(21) being (C₁-C₈)-alkyl, (C₁ -C₈)-perfluoroalkyl, (C₃ -C₈)-alkenyl or --C_(n) H_(2n)--R(24);n being zero, 1, 2, 3 or 4; R(24) being (C₃ -C₈)-cycloalkyl,phenyl, biphenylyl or naphthyl; where the aromatic radicals areunsubstituted or substituted by 1-3 substituents selected from the groupconsisting of F, Cl, CF₃, methyl, methoxy and NR(27)R(28);R(27) andR(28) being H, (C₁ -C₄)-alkyl or (C₁ -C₄)-perfluoroalkyl; R(22) being H,(C₁ -C₈)-alkyl, (C₁ -C₈)-perfluoroalkyl, (C₃ -C₈)-alkenyl or --C_(n)H_(2n) --R(29),n being zero, 1, 2, 3 or 4; R(29) being (C₃-C₈)-cycloalkyl, phenyl, biphenylyl or naphthyl, where the aromaticradicals are unsubstituted or substituted by 1-3 substituents selectedfrom the group consisting of F, Cl, CF₃, methyl, methoxy andNR(30)R(31);R(30) and R(31) being H, (C₁ -C₄)-alkyl or (C₁-C₄)-perfluoroalkyl; R(23) being H, (C₁ -C₄)-alkyl or (C₁-C₄)-perfluoroalkyl; or R(2) is R(33)X--;X is oxygen, S, NR(34) or(D═O)A--;A being oxygen or NR(34); D being C or SO; R(33) being (C₁-C₈)-alkyl, (C₃ -C₈)-alkenyl, (CH₂)_(b) C_(d) F_(2d+1) or --C_(n) H_(2n)--R(36);b is zero or 1; d is 1, 2, 3, 4, 5, 6 or 7; n is zero, 1, 2, 3or 4; R(36) is (C₃ -C₈)-cycloalkyl, phenyl, biphenylyl or naphthyl,where the aromatic radicals are unsubstituted or substituted by 1-3substituents selected from the group consisting of F, Cl, CF₃, methyl,methoxy and NR(37)R(38);R(37) and R(38) being H, (C₁ -C₄)-alkyl or (C₁-C₄)-perfluoroalkyl; R(34) being H, CH₃ or CF₃ ; or R(2) is --SR(40),--OR(40), --NHR(40), --NR(40)R(41), --CHR(40) R(42), -- CR(42)R(43)OH!,--C.tbd.CR(45), --CR(46)═CR(45) or -- CR(47)R(48)!_(u) --(CO)--CR(49)R(50)!_(v) --R(44);R(40) and R(41) are identical or different andare --(CH₂)_(p) --(CHOH)_(q) --(CH₂)r--(CHOH)_(t) R(51) or --(CH₂)_(p)--O--(CH₂ --CH₂ O)_(q) --R(51);R(51) is hydrogen or methyl; u is 1, 2, 3or 4; v is zero, 1, 2, 3 or 4; p, q and r are identical or different andare zero, 1, 2, 3 or 4; t is 1, 2, 3 or 4; R(42) and R(43) are identicalor different and are hydrogen or (C₁ -C₆)-alkyl or, together with thecarbon atom carrying them, form a (C₃ -C₈)-cycloalkyl; R(44) is H, (C₁-C₆)-alkyl, (C₃ -C₈)-cycloalkyl or --C_(e) H_(2e) --R(45);e being zero,1, 2, 3 or 4; R(45) is phenyl, which is unsubstituted or substituted by1-3 substituents selected from the group consisting of F, Cl, CF₃,methyl, methoxy and NR(52)R(53);R(52) and R(53) being H or (C₁-C₄)-alkyl; or R(45) is (C₁ -C₆)-alkyl which is unsubstituted orsubstituted by 1-3 OH; R(46), R(47), R(48), R(49) and R(50) are hydrogenor methyl; R(3) is defined as R(1) or R(2); R(4) and R(5) are,independently of each other, defined as R(2); and pharmaceuticallytolerated salts thereof.
 2. A compound of formula I as claimed in claim1 in which:R(1) is R(6)--CO;R(6) being (C₁ -C₈)-alkyl, CF₃ or --C_(n)H_(2n) --R(9);n being zero, 1, 2, 3 or 4; R(9) being (C₃ -C₈)-cycloalkylor phenyl, where phenyl is unsubstituted or substituted by 1-3substituents selected from the group consisting of F, Cl, CF₃, methyl,methoxy and NR(10)R(11);R(10) and R(11) being H or CH₃ ; R(2) is H, F,Cl, Br, I, OH, CN, (C₁ -C₈)-alkyl, CF₃, (C₃ -C₈)-alkenyl or --C_(n)H_(2n) R(15);n being zero, 1, 2, 3 or 4; R(15) being (C₃ -C₈)-cycloalkylor phenyl, where phenyl is unsubstituted or substituted by 1-3substituents selected from the group consisting of F, Cl, CF₃, methyl,methoxy and NR(16)R(17);R(16) and R(17) being H or CH₃ ; or R(2) isR(21)--SO_(m) ;m being 2; R(21) being (C₁ -C₈)-alkyl, CF₃, (C₃-C₈)-alkenyl or --C_(n) H_(2n) --R(24);n being zero, 1, 2, 3 or 4; R(24)being (C₃ -C₈)-cycloalkyl or phenyl, which is unsubstituted orsubstituted by 1-3 substituents selected from the group consisting of F,Cl, CF₃, methyl, methoxy and NR(27)R(28);R(27) and R(28) being H or CH₃; or R(2) is R(33)X--;X is oxygen, S, NR(34) or (C═O)A--;A being oxygenor NR(34); R(33) being (C₁ -C₈)-alkyl, (CH₂)_(b) C_(d) F_(2d+1) or--C_(n) H_(2n) --R(36);b is zero or 1; d is 1, 2, 3, 4, 5, 6 or 7; n iszero or 1; R(36) is (C₃ -C₈)-cycloalkyl or phenyl, which isunsubstituted or substituted by 1-3 substituents selected from the groupconsisting of F, Cl, CF₃, methyl, methoxy and NR(37)R(38);R(37) andR(38) being H or CH₃ ; R(34) being H or CH₃ ; R(3) is defined as R(1) orR(2); R(4) and R(5) are, independently of each other, defined as R(2).3. A compound of formula I as claimed in claim 1 in which:R(1) isR(6)--CO;R(6) being (C₁ -C₈)-alkyl, CF₃ or --C_(n) H_(2n) --R(9);n beingzero; R(9) being (C₃ -C₈)-cycloalkyl or phenyl, where phenyl isunsubstituted or substituted by 1-3 substituents selected from the groupconsisting of F, Cl, CF₃, methyl, methoxy and NR(10)R(11);R4 R(10) andR(11) being H or CH₃ ; R(2) is H, F, Cl, Br, I, OH, CN, (C₁ -C₈)-alkyl,CF₃ or --C_(n) H_(2n) R(15);n being zero, 1 or 2; R(15) being (C₃-C₈)-cycloalkyl or phenyl, where phenyl is unsubstituted or substitutedby 1-3 substituents selected from the group consisting of F, Cl, CF₃,methyl, methoxy and NR(16)R(17);R(16) and R(17) being H or CH₃ ; or R(2)is R(33)X--;X is oxygen, S or NR(34); R(33) is (C₁ -C₈)-alkyl, (CH₂)_(b)C_(d) F₂₊₁ or --C_(n) H_(2n) --R(36);b is zero or 1; d is 1, 2, 3 or 4;n is zero or 1; R(36) is phenyl, which is unsubstituted or substitutedby 1-3 substituents selected from the group consisting of F, Cl, CF₃,methyl, methoxy and NR(37)R(38);R(37) and R(38) being H or CH₃ ; R(34)being CH₃ ; R(3) is defined as R(1) or is H, F, Cl, Br, I, OH, (C₁-C₈)-alkyl, CF₃ or --C_(n) H_(2n) R(15);n being zero, 1 or 2; R(15)being (C₃ -C₈)-cycloalkyl or phenyl, which is unsubstituted orsubstituted by 1-3 substituents selected from the group consisting of F,Cl, CF₃, methyl, methoxy and NR(16)R(17);R(16) and R(17) being H or CH₃; or R(3) is R(21)--SO_(m) ;m being 2; R(21) being (C₁ -C₄)-alkyl or CF₃; R(4) and R(5) are, independently of each other, hydrogen, F, Cl, OH,CH₃, CF₃, OMe, OCF₃, OH or NH₂.
 4. A compound of formula I as claimed inclaim 1 in which:R(1) is R(6)--CO;R(6) being (C₁ -C₂)-alkyl or --C_(n)H_(2n) --R(9);n being zero; R(9) being phenyl, where phenyl isunsubstituted or substituted by 1-3 substituents selected from the groupconsisting of F, Cl, CF₃, methyl, methoxy and NR(10)R(11);R(10) andR(11) being H or CH₃ ; R(2) is H, F, Cl, Br, I, OH, (C₁ -C₈)-alkyl or--C_(n) H_(2n) R(15);n being zero, 1 or 2; R(15) being (C₃-C₈)-cycloalkyl or phenyl, where phenyl is unsubstituted or substitutedby 1-3 substituents selected from the group consisting of F, Cl, CF₃,methyl, methoxy and NR(16)R(17);R(16) and R(17) being H or CH₃ ; or R(2)is R(33)X--;X is oxygen; R(33) is (C₁ -C₈)-alkyl or --C_(n) H_(2n)--R(36);n is zero or 1; R(36) is phenyl, which is unsubstituted orsubstituted by 1-3 substituents selected from the group consisting of F,Cl, CF₃, methyl, methoxy and NR(37)R(38);R(37) and R(38) being H or CH₃; R(3) is H, F, Cl, Br, l or --C_(n) H_(2n) R(15);n being zero, 1 or 2;R(15) being (C₃ -C₈)-cycloalkyl or phenyl, which is unsubstituted orsubstituted by 1-3 substituents selected from the group consisting of F,Cl, CF₃, methyl, methoxy and NR(16)R(17);R(16) and R(17) being H or CH₃; or R(3) is R(21)--SO_(m) ;m being 2; R(21) being (C₁ -C₄)-alkyl; R(4)and R(5) are, independently of each other, hydrogen, F, Cl, OH, CH₃,CF₃, OMe, OCF₃, OH or NH₂.
 5. A process for preparing a compound I asclaimed in claim 1, wherein a compound of the formula II ##STR7## inwhich R(1) to R(5) have the meaning given in claim 1 and L is a leavinggroup which can readily be substituted by a nucleophile, is reacted withguanidine.
 6. A pharmaceutical composition for treating arrhythmias,which comprises an effective amount for said treatment of a compound offormula I as claimed in claim 1 together with a pharmaceuticallyacceptable carrier.
 7. A method for treating or preventing diseasescaused by ischemic conditions, which comprises administering to a hostin need of said treatment an effective amount of a compound of theformula I as claimed in claim
 1. 8. A diagnostic agent for inhibitingthe Na⁺ /H⁺ exchanger and diagnosing hypertension and proliferativedisorders, which comprises an effective amount for said inhibiting anddiagnosing of a compound of the formula I as claimed in claim
 1. 9. Apharmaceutical composition for treating myocardial infarction, anginapectoris, ischemic conditions of the heart, of the peripheral andcentral nervous systems, of the peripheral organs and limbs, of strokeand of conditions of shock, which comprises an effective amount for saidtreatment of a compound of formula I as claimed in claim 1 together witha pharmaceutically acceptable carrier.
 10. A pharmaceutical compositionfor treating diseases caused by ischemic conditions, which comprises aneffective amount of a compound of formula I or a salt thereof as claimedin claim 1 together with a pharmaceutically acceptable carrier.